The American public was intentionally exposed to spores from the organism Bacillus anthracis in September and October 2001, using the U. S. Mail system as a delivery vehicle. Althoug the event was limited in scope, more than 10,000 people who had potentially been exposed were treated prophylactically with antibiotics. This incident of bioterrorism has heightened awareness of the need to develop a comprehensive and medically sound strategy to deal with B. anthracis as a potential biological weapon. The overarching hypothesis of this proposal is that an in vitro hollow fiber infection model may be applied to the identification of antimicrobial agents and treatment regimens that would be effective against B. anthracis in humans and minimize untoward effects and serve as a powerful tool in designing animal studies directed toward the validation of dosing regimens in humans, utilizing the following experimental strategy: 1.) Evaluation of the efficacy of several classes of antibiotics vs. B. anthracis in an in vitro hollow fiber infection model that simulates human and animal pharmacokinetics. 2.) Isolation and characterization of antibiotic resistant organisms that arise from suboptimal drug exposures. 3.) Evaluation of potential treatment regimens that would be effective against drug-resistant B. anthracis. 4.) Evaluation of treatment regimens effective against Bacillus anthracis for suitability for long-term prophylaxis by testing whether they select for drug resistance in common pathogens such as S. pneumoniae, P. aeruginosa and S. aureus. Together with the projects studing potential treatment regimens for Y. Pestis and Poxviruses, the integration of pharmacodynamic principles and mathematical modeling into these studies offers a unique approach in the optimized design of animal trials in circumstances where randomized clinical trials cannot be performed.